MANAGEMENT OF CHOLELITHIASIS WITH BETA-2-AGONISTS

Abstract: Oral administration of a beta 2-agonist, especially Salbutamol, for the management of episodes of biliary colic in cholelithiasis.

Description: Management of cholelithiasis with beta-2-agonists FIELD OF THE INVENTION This invention relates to the management of cholelithiasis (gall stones) . BACKGROUND OF THE INVENTION In cholelithiasis, calculi usually of cholesterol-related material but sometimes of calcium salts, are present in the gall bladder. The calculi themselves are harmless and are asymptomatic in many people but there are episodes of biliary colic when the gall bladder wall, which includes smooth muscle, meeting resistance or friction from the calculi, contracts and is stimulated to further contraction. This is experienced by the patient as pain which can reach extremely severe levels * . If frequently repeated they lead to a pathological state of the gall bladder. At present there is no effective treatment for the condition; acute attacks are treated for pain relief only, usually by the administration of morphine, after which surgical intervention is the only solution except in the minority of cases, where the calculi are of calcium salts when they may be able to be dispersed by ultrasound treatment. The proper management of such cases is therefore one of considerable economic and medical importance; in the United Kingdom gall bladder removal is the commonest abdominal operation. SUMMARY OF THE INVENTION The present invention provides for the effective management of cholelithiasis. It consists in the administration of an effective amount of an agent which will raise the resting difference in potential across the plasma membrane of the smooth muscle cells in the wall of the gall bladder. A preferred agent is a known smooth muscle relaxant, especially of the class known as S2-agonists. Most preferred amongst these is Salbutamol (2-tert-butylamino-l- (4-hydroxy-3- hydroxymethylphenyl) ethanol) . Administration will preferably be orally. The invention also provides for the use of such an agent, of a smooth muscle relaxant and in particular of a smooth muscle relaxant which is a β2- agonist in the manufacture of a medicament for the management of cholelithiasis. The medicament will be preferably in tablet form. Such agents are known. One of the earliest- known of the general class is ephedrine. This is effective in the present invention but is not specific and therefore has side-effects; pseudoephedrine is similar. These and other general relaxants have been largely superceded by groups of relaxants which are targetted and indicated for various different specific organs of the body. The β2-agonists with which the present invention is particularly concerned are formulated and indicated for the treatment of asthma and as such are most commonly presented in aerosol or spray form, for inhalation by the patient. However, tablet forms are also available. It is known that at least some &2-agonists, including Salbutamol, have an effect on the uterus and have been used for the inhibition of contractions during premature labour. However, no connection has been made to the best of my knowledge between any such agent, any smooth muscle relaxant and particularly not any member of the S2-agonist group of relaxants, and the management of cholelithiasis. Although Salbutamol is the preferred S2- agonist relaxant used in this invention (examples of formulation being Ventolin from Glaxo, Salbuvent from Tillots, Salbulin from Riker and Volmax from Duncan Flockhart) other β-agonists which may be used include those known under the generic names Salmeterol ( (RS) -5- {l-hydroxy-2- [6- (phenylbutoxy)hexylamino] ethyl}salinyl alcohol) , Orciprenaline (1- (3, 5-dihydroxyphenyl) -2- isopropylamino ethanol sulphate) , Terbutaline (2-tert- butylamino-1- (3, 5-dihydroxyphenyl) ethanol sulphate) , Fenoterol (1- (3, 5-Dihydroxyphenyl) -2- (4-hydroxy-α.- methylphenethylamino) ethanol hydrobromide) , Reproterol (7-{3- [ (3 , 5,β-trihydroxyphethyl) amino] propyl}theophylline hydrochloride) , Rimiterol (ervthro- (3,4-dihydroxyphenyl) (2-piperidyl)methanol hydrobromide) and Isoetharine (1- (3,4-dihydroxyphenyl) - 2-isopropylamino butan-1-ol hydrochloride) . In the present treatments the agent is preferably administered sublingually by tablet despite the fact that relief would not usually be experienced for some forty minutes. Dosages may be in the range presently prescribed for asthma. When administered orally a single 4mg tablet of Salbutamol held sublingually will give relief to an average patient after a delay of some forty minutes, lasting for the whole of the usual duration of an episode which is about four hours. Management of an acute episode will usually be in hospital because of the severity of the pain experienced. Tenderness (inflammation) of the gall¬ bladder following an acute episode may be treated by steroids such as β-methazone by injection. The chronic condition can be managed by the patient himself upon feeling the onset of an episode, preferably by sublingual tablet. As is conventional the patient should adopt a favourable regime and in particular avoid a high fat diet. EXAMPLE OF SPECIFIC EMBODIMENTS The treatment has been tested on myself. Knowing that I had the condition confirmed by ultrasonography, having for particular reasons postponed surgical intervention, and feeling the onset of a further episode of pain I administered 30mg of ephedrine hydrochloride to myself sublingually and within fifteen minutes had partially averted pain which in earlier episodes had been extremely severe: I then administered another 30mg to myself by the same route and experienced complete relief of the biliary colic within a further fifteen minutes. However, I suffered the usual side-effects of ephedrine. On the next occasion I administered by the same route a single 4mg tablet of Salbutamol ("Ventolin" ) . This brought total relief within forty minutes. I have continued this management regime using Salbutamol 4mg for three years and have averted a further twelve episodes of pain by it without any side effects, and thereby rendering surgical intervention unnecessary. In each case I waited for the appearance of the diagnostic right upper quadrant tenderness before administration. Conventional analgesia should be avoided at times when the present treatments are being followed.

Claims: AMENDED CLAIMS [received by the International Bureau on 12 August 1994 (12.08.94) original claims 1-14 replaced by amended claims 1-14 (2 pages)] 1. Use of a β2-agonist in the manufacture of a preparation for the management of gall stones in the gall bladder. 2. Use according to claim 1 wherein the β2- agonist is Salbutamol. 3. Use according to claim 1 or claim 2 wherein the preparation is for oral administration. 4. Use according to claim 3 wherein the preparation is in the form of 4 mg tablets of Salbutamol . 5. A medicament for the management of gall stones in the gall bladder, comprising a β2-agonist as effective ingredient. 6. A medicament according to claim 5 wherein the β2-agonist is Salbutamol. 7. A medicament according to claim 6 in the form of 4 mg tablets of Salbutamol . 8. Method for the management of gall stone in the gall bladder of a patient which comprises administering to the patient an effective amount of a β2-agonist . 9. Method according to claim 8 wherein the β2- agonist is Salbutamol. 10. Method according to claim 8 wherein the administration is sublingual. 14. Method according to claim 9 wherein the 7 administration is sublingual.

Inventors: WRIGHT GEORGE HENRY, WRIGHT, GEORGE, HENRY
Applicants: WRIGHT GEORGE HENRY, WRIGHT, GEORGE, HENRY
Application year: 1994
Main classification: A61K31
IPC codes: A61K31